Protein kinases have gained acceptance as therapeutic targets and have become a major focus of drug development efforts in oncology, with hundreds of inhibitors either in the pipeline or already in the clinic. Protein phosphatases, on the other hand, have been largely ignored for drug development because of their reputed lack of substrate specificity and the toxicity associated with natural products discovered as potent active site inhibitors.
Protein phosphatase 2A (PP2A) is one of the four major serine threonine phosphatases and is implicated in the negative control of cell growth and division. PP2A can dephosphorylate key oncogenic signaling proteins to function as a tumor suppressor. The PP2A protein phosphatase is a ubiquitous and conserved phosphatase with broad substrate specificity and diverse cellular functions. In contrast to the narrow substrate specificity of protein kinases, PP2A interacts with multiple substrates, and therefore its activation is, in effect, a combination therapy that coordinately inhibits multiple signaling pathways, including oncogenic signaling pathways. Among the targets of PP2A are proteins of oncogenic signaling cascades, such as Raf, MEK, AKT, ERK and FOXO.